Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Inclusion Criteria: * 1\. Female, Age ≥ 18 years * 2\. Histologic or cytologic confirmation of HER2-amplified breast cancer according to most recent biopsy (local testing permitted) * a. HER2-amplified status is defined as a HER2/CEP17 ratio ≥2 or an average of ≥6 HER2 gene copies per cell by in situ hybridization (ISH) according to the 2013 American Society of Clinical Oncology (ASCO)/CAP guidelines * 3\. Measurable or evaluable metastatic disease by RECIST (v1.1). * 4\. Progression of disease on or ≤6 months of completing prior TDM1 therapy * 5\. ≤ 4 prior chemotherapy regimens for MBC (Phase I portion) or ≤ 3 prior chemotherapy regimens for MBC (Phase II portion) * 6\. Adequate hematologic function independent of transfusion and growth factor support for ≤7 days prior to screening, with the exception of pegylated G-CSF (pegfilgrastim) and darbepoetin which require discontinuation at least 14 days prior to screening, defined as: * Absolute neutrophil count \>1500 cells/mm3 (0.75 x 10\^9/L). * Platelet count \>100,000 cells/mm3 (50 x 10\^9/L). * Hemoglobin \>9.0 g/dL. * 7\. Adequate hepatic and renal function defined as: * Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper limit of normal (ULN) if liver metastases, or ≤3 x ULN in the absence of liver metastases. * Alkaline phosphatase \<2.5 x ULN, unless bone metastases are present and in the absence of liver metastases * Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault) * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, such as hemolysis) * 8\. Prothrombin time (PT)/international normalized ratio (INR) \< 1.5xULN and PTT (aPTT) \< 1.5x ULN * 9\. Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline as determined by either ECHO or multiple gated acquisition scan (MUGA) and within normal limits per institutional guidelines * 10\. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * 11\. Negative urine/serum pregnancy test within 72 hours before starting study medications for women of childbearing potential * 12\. Women of childbearing potential who agree to use two highly effective methods of birth control (e.g., some intrauterine devices \[IUD\], diaphragm with spermicide, condom with spermicide, sterilized partner, or complete abstinence) for the duration of the study and for 30 days after the last dose of study drug o Note: Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms), or if they have undergone surgical sterilization * 13\. Signed informed consent obtained prior to any screening procedures. * 14\. Signed Patient Authorization Form (HIPAA) obtained prior to any screening procedures. Exclusion Criteria: * 1\. Uncontrolled or untreated central nervous system metastases, defined as clinical or radiologic evidence of progression of brain metastases or clinical signs of leptomeningeal disease 1. Patients with treated brain metastases are eligible provided they do not have clinical or radiologic evidence of disease progression and have been off of dexamethasone for ≥2 weeks prior to first dose of study drugs 2. Brain MRI at baseline required for patients with known brain metastases at study entry * 2\. Chemotherapy ≤ 21 days prior to first administration of study treatment * 3\. History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated carcinoma in situ without evidence of disease. * 4\. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration days\] \[ \> 14 days\] of \>5 mg/day of prednisone) ≤28 days of the first dose of study drug. * 5\. Vaccinated with live, attenuated vaccines ≤4 weeks of first dose of study drug. * 6\. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug. * 7\. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. * 8\. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. * 9\. History of stroke or intracranial hemorrhage ≤6 months prior to first dose of study drug. * 10\. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. * 11\. Any uncontrolled active systemic infection. * 12\. Major surgery ≤ 4 weeks of first dose of study drug. * 13\. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk. * 14\. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization. * 15\. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. * 16\. Concomitant use of warfarin or other Vitamin K antagonists. * 17\. Receipt of a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or requirement for continuous treatment with a strong CYP3A inhibitor. * 18\. Chronic liver disease with hepatic impairment Child-Pugh class B or C. * 19\. Lactating or pregnant. * 20\. Unwilling or unable to participate in all required study evaluations and procedures. * 21\. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).